Cycloalkylamides of (8 beta )-1-alkyl-6-(substituted)ergolines

ABSTRACT

This invention provides (8 beta )-1-cycloalkyl-1-alkyl-6-(substituted)ergoline-8-carboxamides useful for blocking 5HT2 receptors in mammals having an excess of serotonin centrally or peripherally. The invention also provides methods for treating sexual dysfunction, hypertension, migraine, vasospasm, thrombosis, ischemia, depression, anxiety, sleep disorders and appetite disorders with a compound of the invention. This is a Division of U.S. Ser. No. 394,320, which is a continuation of U.S. Ser. No. 62,285, Jun. 15, 1981, abandoned. The present invention relates to a compound of the formula   &lt;IMAGE&gt;   wherein: R1 is C1-C4 alkyl; R2 is allyl or C1-C4 straight chain alkyl; R3 is hydrogen or C1-C4 straight chain alkyl; R4 is hydrogen, C1-C4 alkyl, hydroxy or C1-C4 alkoxy; m is 0, 1, 2 or 3; and the pharmaceutically acceptable acid addition salts thereof. The present invention also provides pharmaceutical formulations comprising, and methods of using, compounds of the invention. DETAILED DESCRIPTION OF THE INVENTION In the above formula, the term &#34;C1-C4 alkyl&#34; represents a straight or branched alkyl chain having from one to four carbon atoms. Typical C1-C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl and the like. C1-C4 Straight chain alkyl represents a straight, but not branched, alkyl chain having from one to four carbon atoms. C1-C4 Straight chain alkyl groups are methyl, ethyl, n-propyl and n-butyl. C1-C4 Alkoxy represents a straight or branched alkoxy chain having from one to four carbon atoms. Typical C1-C4 alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and the like. When m is 0, the ring attached to the amide nitrogen atom is cyclopentyl; when m is 1, the ring is cyclohexyl; when m is 2, the ring is cycloheptyl; and when m is 3, the ring is cyclooctyl. If the cycloalkyl ring is substituted, the substituent may be at any available position on the ring. While all of the compounds of the present invention are believed useful for blocking 5HT2 receptors in mammals, certain of the compounds are preferred for such use. Preferably, R1 is isopropyl. Also, R2 is preferably methyl, R3 is hydrogen, and m is 1. R4 is preferably hydrogen. Other preferred aspects of the present invention will be noted hereinafter. Compounds of the present invention are named as ergoline derivatives in which the trans(-) or 5R,10R configuration of the bridgehead hydrogens is specified. This is the same configuration as in the naturally-occurring 9,10-dihydro ergot alkaloids. In U.S. Pat. No. 3,580,916, a different naming system is used. The basic ring system is named as a 6aR,10aR-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-f,g]-quinoline. Illustratively, by the alternate naming system, 9,10-dihydrolysergic acid becomes 6aR,10aR-7-methyl-4,6,6a,7,8,9,10,10a-octahydroindolo[4,3-f,g]-quinoli ne-9 beta -carboxylic acid. Another equally valid name for dihydrolysergic acid is (8 beta )-6-methylergoline-8-carboxylic acid. The trivial name &#34;ergoline&#34; will be employed herein with the numbering system specified above for compounds of the invention. While the configuration at asymmetric carbons 5,8 and 10 in the above formula is set as 5 beta , 8 beta  and 10 alpha , generally speaking, the substituted cycloalkyl amide group contains two additional asymmetric carbons. For example, 3-methoxycyclohexylamide exists as two racemates, each racemate containing two enantiomers or stereoisomers. However, where the substituted cycloalkylamide possesses a plane of symmetry, mirror images turn out to be superimposable, and the compound actually exists in only two forms. These forms are designated as the cis form and the trans form, drawn for convenience in two dimensions as Ia and Ib.    &lt;IMAGE&gt; Ia &lt;IMAGE&gt; Ib  When an amide of a (8 beta )-6-methylergoline-8-carboxylic acid is formed with a cis or trans 4-substituted cycloalkyl amine, the product will be a single geometrical isomer. In general, the two amides in this instance will also be named, for the sake of simplicity, as cis and trans (4-substituted)cycloalkyl amides. This invention contemplates all such forms useful for blocking 5HT2 receptors in mammals; that is, the individual diastereoisomers and geometrical isomers as well as racemates. Pharmaceutically-acceptable acid addition salts of the compounds of the invention include salts derived from non-toxic inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, phosphorous acid and the like, as well as salts derived from non-toxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, alkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Such pharmaceutically-acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,  beta -hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate and like salts. The following examples further illustrate specific compounds of the present invention: (8 beta )-N-Cyclohexyl-1-isopropyl-6-n-butylergoline-8-carboxamide (8 beta )-N-(3-Methylcyclopentyl)-1-sec.-butyl-6-methylergoline-8-carboxamide maleate (8 beta )-N-Cycloheptyl-1,6-diethylergoline-8-carboxamide nitrate (8 beta )-N-Cyclohexyl-N-ethyl-1-isopropyl-6-methylergoline-8-carboxamide (8 beta )-trans-N-(4-Methoxycyclooctyl)-1-isopropyl-6-methylergoline-8-carboxa mide hydrochloride (8 beta )-N-Cycloheptyl-N-methyl-1-isopropyl-6-n-propylergoline-8-carboxamide (8 beta )-N-Cyclohexyl-1-t-butyl-6-n-propylergoline-8-carboxamide (8 beta )-N-Cyclohexyl-1-t-butyl-6-methylergoline-8-carboxamide succinate (8 beta )-cis-N-(4-Methylcyclohexyl)-1-ethyl-6-methylergoline-8-carboxamide citrate (8 beta )-N-Cyclopentyl-1-sec.-butyl-6-methylergoline-8-carboxamide lactate (8 beta )-N-Cyclohexyl)-N-n-propyl-1-isopropyl-6-methylergoline-8-carboxamide (8 beta )-N-Cyclopentyl-N-methyl-1-n-butyl-6-n-butylergoline-8-carboxamide (8 beta )-N-Cyclohexyl-1-isopropyl-6-n-allylergoline-8-carboxamide acetate (8 beta )-N-Cyclooctyl-1-isopropyl-6-methylergoline-8-carboxamide (8 beta )-N-Cycloheptyl-1-n-propyl-6-methylergoline-8-carboxamide maleate (8 beta )-N-Cyclohexyl-1,6-di(n-propyl)ergoline-8-carboxamide (8 beta )-N-Cyclopentyl-N-methyl-1,6-dimethylergoline-8-carboxamide (8 beta )-cis-N-(4-Hydroxycycloheptyl)-1,6-diethylergoline-8-carboxamide (8 beta )-N-Cyclopentyl-1-isopropyl-6-ethylergoline-8-carboxamide hydrobromide (8 beta )-N-(4-Hydroxycyclohexyl)-1-n-butyl-6-methylergoline-8-carboxamide malonate (8 beta )-N-Cyclohexyl-1-n-butyl-6-n-propylergoline-8-carboxamide (8 beta )-N-Cycloheptyl-1-n-butyl-6-methylergoline-8-carboxamide (8 beta )-N-(4-Methylcyclohexyl)-N-methyl-1-n-propyl-6-methylergoline-8-carbox amide malate (8 beta )-N-(3-Methylcyclooctyl)-N-methyl-1-isopropyl-6-allylergoline-8-carbox amide (8 beta )-N-Cyclooctyl-1-sec.-butyl-6-methylergoline-8-carboxamide tartrate (8 beta )-N-(4-Methoxycyclohexyl)-1-isopropyl-6-n-butylergoline-8-carboxamide (8 beta )-N-Cycloheptyl-1-methyl-6-methylergoline-8-carboxamide oxalate (8 beta )-cis-N-(4-Hydroxycyclohexyl)-N-n-propyl-1-methyl-6-n-propylergoline-8 -carboxamide (8 beta )-N-Cyclopentyl-1-t-butyl-6-methylergoline-8-carboxamide (8 beta )-N-Cyclohexyl-1,6-diethylergoline-8-carboxamide (8 beta )-N-(3-Methylcyclohexyl)-1-isopropyl-6-n-propylergoline-8-carboxa



